D-Tocotrienols possess a number of properties that can aid in the treatment of various human diseases. In particular, D-gamma-tocotrienol is reported to have several beneficial physiological effects in humans. D-gamma-tocotrienol is a substance that occurs naturally at low levels in many plant tissues (see Bauernfield in "Vitamin E, A Comprehensive Treatise," ed. L. Machlin, Marcel Dekker, New York, 1980, pp. 99-167). D-gamma-tocotrienol possesses antitumor activity (see Kato et al., J. Jpn. Oil Chemists Soc. 34, pp. 375, 1985; Komiyama et al., Chem. Pharm, Bull. 37, pp. 1369, 1989), antihypercholesterolemic activity (see Qureshi et al., Am. J Clin. Nutr. 53, pp. 1021S, 1991; Watkins et al., Lipids 28, pp. 1113, 1993; Tan et al., Am. J Clin. Nutr. 53, pp. 1027S, 1991; Parker et al., J. Biol. Chem. 268, pp. 11230, 1993; European Patent Application No. 90119040.5, and U.S. Pat. No. 5,217,992), and antioxidant activity (see Yamaoka et al., J. Am. Oil Chemists Soc. 68, pp. 114, 1991). Thus, D-tocotrienols are useful as pharmaceutical materials and as nutritional supplements.
One problem associated with naturally-occurring D-tocotrienols is their poor solubility or insolubility in water. The poor solubility in water limits the ability of D-tocotrienols to be admixed with other components in an aqueous media. The poor solubility of tocotrienols also limits their usefulness for parental injection. The prior art does not disclose a method for overcoming this problem. Thus, one object of the present invention is to increase the water-solubility of D-tocotrienols.
The prior art discloses the preparation of water-soluble tocopherol compounds. U.S. Pat. No. 2,680,749 to Cawley et al.; U.S. Pat. No. 3,102,078 to Robeson et al.; U.S. Pat. No. 5,430,021 to Rudnic et al.; and International Publication No. WO 95/31217 to Sonne disclose polyethoxylated succinate esters of tocopherol. These references, however, do not disclose the preparation of polyethoxylated succinate esters of tocotrienols, particularly of D-tocotrienols.
The prior art also discloses the synthesis of succinate esters of tocotrienols (see U.S. Pat. No. 5,348,974 to Wright et al.; U.S. Pat. No. 5,554,647 to Perricone; European Patent Publication No. 0571928 A1 to Pearce; European Patent Publication No. 0669132 A1 to Liqui; Japanese Patent Application No. 61060619; and Goh et al., J. Am. Oil Chem. Soc., 67, pp 250-254, 1990). These references, however, do not disclose polyethoxylating the tocotrienol succinate esters. Additionally, these references only disclose the preparation of succinate esters of racemic mixtures of tocotrienols and not the D-enantiomer.
Korean Patent Application No. 9507722 B to Ha et al. discloses a composition for skin detergent possessing protective properties against UV light. The composition contains polyethoxylated tocopherols or tocotrienols and its ester thereof. These compounds are not a feature of the present invention. Moreover, there is no disclosure in Ha et al. for preparing the succinate ester of D-tocotrienols.
In light of the above, it would be very desirable to produce water-dispersible D-tocotrienol compounds that can be used as pharmaceutical materials and nutritional supplements.